FGL1-hepcidin axis in iron homeostasis and disease

Systemic iron homeostasis is governed by hepcidin through regulation of the iron exporter ferroportin. Hepcidin expression is primarily regulated by the bone morphogenetic protein (BMP)-SMAD signaling pathway, which integrates signals from iron status, erythropoietic demand, and inflammation. Fibrinogen-like protein 1 (FGL1) has recently emerged as a hepatocyte-derived regulator of this axis. FGL1 is a secreted hepatokine which is induced by hypoxia, inflammatory signaling, and metabolic stress. FGL1 suppresses hepcidin by binding BMP ligands, thereby attenuating BMP-SMAD signaling and reducing HAMP transcription. This mechanism complements erythroferrone (ERFE), providing a sustained hepatocyte-derived signal during anemia/ hypoxia and erythropoietic stress. Beyond iron regulation, FGL1 functions as a ligand of lymphocyte activation gene-3 (LAG-3), linking iron metabolism with immune checkpoint pathways. This dual role establishes FGL1 at the interface of metabolic and immune regulation. Dysregulation of FGL1 has been implicated in multiple disease states. In chronic kidney disease, reduced circulating FGL1 may contribute to hepcidin excess and functional iron deficiency. In autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's disease, FGL1 exhibits context-dependent effects on immune regulation. In cancer, tumor-derived FGL1 promotes immune evasion through the FGL1-LAG-3 axis and is associated with resistance to PD-(L)1 blockade and poor clinical outcomes. This review provides a comprehensive overview of FGL1 structure, regulation, and function. It also highlights its emerging role as a mediator linking iron metabolism and immune regulation, as well as its potential as a biomarker.